rs150384171

Positions:

• chr19-8305034-ACTC-A
• chr19-8305034-ACTC-ACTCCTC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_Supporting BS2

The NM_016579.4(CD320):​c.262_264del​(p.Glu88del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,606,154 control chromosomes in the GnomAD database, including 102 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0080 (7 hom., cov: 33)
  • Exomes 𝑓: 0.011 (95 hom.)
• Consequence: CD320 NM_016579.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 B:4 O:1
• Conservation: PhyloP100: 0.450

Genes affected

CD320 (HGNC:16692): (CD320 molecule) This gene encodes the transcobalamin receptor that is expressed at the cell surface. It mediates the cellular uptake of transcobalamin bound cobalamin (vitamin B12), and is involved in B-cell proliferation and immunoglobulin secretion. Mutations in this gene are associated with methylmalonic aciduria. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_016579.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD320	NM_016579.4	c.262_264del	p.Glu88del	inframe_deletion	2/5	ENST00000301458.10	NP_057663.1
CD320	NM_001165895.2	c.143-949_143-947del		intron_variant			NP_001159367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD320	ENST00000301458.10	c.262_264del	p.Glu88del	inframe_deletion	2/5	1	NM_016579.4	ENSP00000301458	P1

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1216 AN: 151518 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00293

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.00271

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00673

GnomAD3 exomes AF: 0.00936 AC: 2299 AN: 245504 Hom.: 12 AF XY: 0.00905 AC XY: 1207 AN XY: 133364

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0124

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00437

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00837

GnomAD4 exome AF: 0.0110 AC: 15935 AN: 1454522 Hom.: 95 AF XY: 0.0107 AC XY: 7730 AN XY: 723916

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.0140

Gnomad4 ASJ exome AF: 0.00965

Gnomad4 EAS exome AF: 0.0102

Gnomad4 SAS exome AF: 0.00322

Gnomad4 FIN exome AF: 0.00372

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00802 AC: 1216 AN: 151632 Hom.: 7 Cov.: 33 AF XY: 0.00791 AC XY: 586 AN XY: 74058

Gnomad4 AFR AF: 0.00292

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.0125

Gnomad4 SAS AF: 0.00271

Gnomad4 FIN AF: 0.00315

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00666

Alfa AF: 0.00232 Hom.: 1

Bravo AF: 0.00830

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic acidemia due to transcobalamin receptor defect Pathogenic:2 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This variant, c.262_264del, results in the deletion of 1 amino acid(s) of the CD320 protein (p.Glu88del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs150384171, gnomAD 1.4%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with methylmalonic aciduria (PMID: 20524213, 22819238, 29663633, 34978764; Invitae). ClinVar contains an entry for this variant (Variation ID: 203643). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CD320 function (PMID: 20524213, 27411955). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Benign:3 Other:1

other, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2017	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2018	This variant is associated with the following publications: (PMID: 20524213, 29040465, 29663633, 30041674, 22819238, 31180159, 31462756) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CD320: PM4:Supporting, BS1, BS2 -

CD320-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2024

The CD320 c.262_264delGAG variant is predicted to result in an in-frame deletion (p.Glu88del). This variant has been reported in the homozygous or compound heterozygous state in patients with methylmalonic acidemia and homocysteinemia due to transcobalamin receptor deficiency (e.g., Quadros et al. 2010. PubMed ID: 20524213; Karth et al. 2012. PubMed ID: 22819238; Hannah-Shmouni et al. 2018. PubMed ID: 29663633; Pappas et al. 2022. PubMed ID: 34978764). Fibroblast cells from patients apparently homozygous for the CD320 c.262_264del (p.Glu88del) variant showed reduced uptake of holo-transcobalamin (holo-TC) as well as elevated levels of homocysteine and methylmalonic acid in culture medium (Quadros et al. 2010. PubMed ID: 20524213; Pangilinan et al. 2022. PubMed ID: 35107211). The c.262_264del variant has been reported in a large population database at an allele frequency of up to ~1.4%, which would be high for an autosomal recessive disorder with a severe phenotype. It should be noted, however, that most reported patients with transcobalamin receptor deficiency have been clinically asymptomatic. These data suggest that this may possibly be a benign biochemical phenotype, although the long-term outcome in these individuals is not currently well understood (Hannah-Shmouni et al. 2018. PubMed ID: 29663633). In summary, we classify the c.262_264del (p.Glu88del) variant as likely pathogenic for recessive transcobalamin receptor deficiency. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150384171; hg19: chr19-8369918;